Skip to main content

Advertisement

SpringerLink
Log in

miR-137 Is Frequently Down-Regulated in Gastric Cancer and Is a Negative Regulator of Cdc42

  • Original Article
  • Published:
Digestive Diseases and Sciences Aims and scope Submit manuscript

Abstract

Introduction

MicroRNAs (miRNAs) are a class of small (19–25 nucleotides) noncoding RNAs that regulate the expressions of a wide variety of genes, including some involved in cancer development. Some recent studies show that DNA methylation contributes to down-regulation of microRNA-137 (miR-137) during tumorigenesis. Whether down-regulation of miR-137 also exists in gastric cancer is unknown.

Aim

Our aim was to test the hypothesis that down-regulation of miR-137 also exists in gastric cancer.

Methods

Expression of levels of miR-137 were examined using real-time PCR on paired gastric cancer and adjacent non-cancerous tissues. The methylation status is detected by MSP.

Results

Results show that miR-137 is downregulated by hypermethylation of the promoter in gastric cancer tissues. Epigenetic silencing of miR-137 induced an up-regulation of its targets, Cdc42. Restoration of the miR-137 expression in gastric cancer cell lines downregulated the Cdc42 expression. Restoration of the miR-137 and inactivation of Cdc42 induce apoptosis and cell cycle G1 arrest in gastric cancer cells. Furthermore, the miR-137 expression was found to be inversely correlated with CDC42 expression in gastric caner.

Conclusions

miR-137 is frequently down-regulated in gastric cancer and is a negative regulator of Cdc42.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Zhang B, Pan X, Cobb GP, Anderson TA. MicroRNAs as oncogenes and tumor suppressors. Dev Biol. 2007;302:1–12.

    Article  PubMed  CAS  Google Scholar 

  2. Miska EA. How microRNAs control cell division, differentiation and death. Curr Opin Genet Dev. 2005;15:563–568.

    Article  PubMed  CAS  Google Scholar 

  3. Huang YW, Liu JC, Deatherage DE, et al. Epigenetic repression of microRNA-129–2 leads to overexpression of sox4 oncogene in endometrial cancer. Cancer Res. 2009;69:9038–9046.

    Article  PubMed  CAS  Google Scholar 

  4. Dyrskjot L, Ostenfeld MS, Bramsen JB, et al. Genomic profiling of microRNAs in bladder cancer: Mir-129 is associated with poor outcome and promotes cell death in vitro. Cancer Res. 2009;69:4851–4860.

    Article  PubMed  CAS  Google Scholar 

  5. Kozaki K, Imoto I, Mogi S, Omura K, Inazawa J. Exploration of tumor-suppressive microRNAs silenced by DNA hypermethylation in oral cancer. Cancer Res. 2008;68:2094–2105.

    Article  PubMed  CAS  Google Scholar 

  6. Silber J, Lim DA, Petritsch C, et al. Mir-124 and mir-137 inhibit proliferation of glioblastoma multiforme cells and induce differentiation of brain tumor stem cells. BMC Med. 2008;6:14.

    Article  PubMed  Google Scholar 

  7. Bemis LT, Chen R, Amato CM, et al. Microrna-137 targets microphthalmia-associated transcription factor in melanoma cell lines. Cancer Res. 2008;68:1362–1368.

    Article  PubMed  CAS  Google Scholar 

  8. Liu M, Lang N, Qiu M, Xu F, Li Q, Tang Q, Chen J, Chen X, Zhang S, Liu Z, Zhou J, Zhu Y, Deng Y, Zheng Y, Bi F. Mir-137 targets cdc42 expression, induces cell cycle g1 arrest, and inhibits invasion in colorectal cancer cells. Accepted in Int J Cancer.

  9. Balaguer F, Link A, Lozano JJ, Cuatrecasas M, Nagasaka T, Boland CR, Goel A. Epigenetic silencing of mir-137 is an early event in colorectal carcinogenesis. Cancer Res. 2010;70:6609–6618.

    Article  PubMed  CAS  Google Scholar 

  10. Langevin SM, Stone RA, Bunker CH, Grandis JR, Sobol RW, Taioli E. Microrna-137 promoter methylation in oral rinses from patients with squamous cell carcinoma of the head and neck is associated with gender and body mass index. Carcinogenesis. 2010;31:864–870.

    Article  PubMed  CAS  Google Scholar 

  11. Szczur K, Zheng Y, Filippi MD. The small Rho GTPase Cdc42 regulates neutrophil polarity via CD11b integrin signaling. Blood. 2009;114:4527–4537.

    Article  PubMed  CAS  Google Scholar 

  12. Feng Y, Hartig SM, Bechill JE, Blanchard EG, Caudell E, Corey SJ. The cdc42-interacting protein-4 (cip4) gene knock-out mouse reveals delayed and decreased endocytosis. J Biol Chem. 2010;285:4348–4354.

    Article  PubMed  CAS  Google Scholar 

  13. Gomez Del Pulgar T, Valdes-Mora F, Bandres E, et al. Cdc42 is highly expressed in colorectal adenocarcinoma and downregulates ID4 through an epigenetic mechanism. Int J Oncol. 2008;33:185–193.

    PubMed  Google Scholar 

  14. Sahai E, Marshall CJ. Rho-GTPases and cancer. Nat Rev Cancer. 2002;2:133–142.

    Article  PubMed  Google Scholar 

  15. Kamai T, Yamanishi T, Shirataki H, et al. Overexpression of RhoA, Rac1, and Cdc42 GTPases is associated with progression in testicular cancer. Clin Cancer Res. 2004;10:4799–4805.

    Article  PubMed  CAS  Google Scholar 

  16. Yang L, Wang L, Zheng Y. Gene targeting of Cdc42 and Cdc42GAP affirms the critical involvement of Cdc42 in filopodia induction, directed migration, and proliferation in primary mouse embryonic fibroblasts. Mol Biol Cell. 2006;17:4675–4685.

    Article  PubMed  CAS  Google Scholar 

  17. Zugasti O, Rul W, Roux P, et al. Raf-MEK-Erk cascade in anoikis is controlled by Rac1 and Cdc42 via Akt. Mol Cell Biol. 2001;21:6706–6717.

    Article  PubMed  CAS  Google Scholar 

Download references

Conflict of interest

The author(s) declare that they have no competing interests.

Author information

Authors and Affiliations

  1. Department of Medicine-Oncology, The First Affiliated Hospital, Zhengzhou University, 1 East Jianshe Road, 450000, Zhengzhou, People’s Republic of China

    Qingjiang Chen, Mingzhi Zhang & Qingxia Fan

  2. Department of Internal Medicine-Oncology, Henan Cancer Hospital, The Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, People’s Republic of China

    Xiaobing Chen, Suxia Luo & Xinguang Cao

Authors
  1. Qingjiang Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xiaobing Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Mingzhi Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Qingxia Fan
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Suxia Luo
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Xinguang Cao
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Mingzhi Zhang.

Additional information

Qingjiang Chen and Xiaobing Chen contributed equally to this work.

Electronic supplementary material

Below is the link to the electronic supplementary material.

10620_2010_1536_MOESM1_ESM.jpg

MKN45 cells were subjected to Western blot analysis using antibodies against Cdc42, the phosphorylated form of ERK1/2, total ERK1/2 and Actin. Actin was used as an internal control. (JPEG 33 kb)

10620_2010_1536_MOESM2_ESM.jpg

The expression of Cdc-42 in gastric cancer cell lines MKN45 treated with or without demethylation agent DAC as determined by Western blot. Actin was used as an internal control. (JPEG 74 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Chen, Q., Chen, X., Zhang, M. et al. miR-137 Is Frequently Down-Regulated in Gastric Cancer and Is a Negative Regulator of Cdc42. Dig Dis Sci 56, 2009–2016 (2011). https://doi.org/10.1007/s10620-010-1536-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10620-010-1536-3

Keywords

Search

Navigation